Platinum anticancer agents comprise an essential component in the current repertoire of chemotherapeutics. Cisplatin and carboplatin have been used to successfully treat testicular, cervical, ovarian, and non-small cell lung cancers. However, cancers that exhibit deficiencies in the DNA mismatch repair (MMR) machinery are largely resistant to cisplatin treatment, as MMR proteins are among those responsible for the recognition of Pt-DNA lesions. MMR-deficient cancers, including 15% of sporadic colorectal cancer cases and 18% of all solid tumors, can be treated in part with oxaliplatin, which employs a trans 1,2-diaminocyclohexane non-leaving group ligand instead of the amines. As a result, oxaliplatin-DNA adducts are poorly recognized by MMR proteins, rendering the drug highly effective against cisplatin-resistant cancers in vitro. However, the efficacy of oxaliplatin in vivo is severely limited, and treatment must be administered in combination with a variety of drugs, such as 5-fluorouracil and leucovorin. Although this combinatorial approach does increase the response rate of oxaliplatin treatment, the improvement is modest, and the overall efficacy in the later stages of colorectal cancer is still very low.
Bulky, octahedral rhodium (III) complexes, called metalloinsertors, bind DNA specifically at lesions containing base pair mismatches. This selectivity is achieved through metalloinsertion, a general binding mode in which a sterically expansive ligand inserts into the base stack at the site of the thermodynamically destabilized mismatch, ejecting the mismatched bases from the duplex. As this recognition event occurs with high affinity and over 1000 fold selectivity, metalloinsertors offer a promising alternative in the treatment of MMR-deficient cancers.